hydrogen sulfide / Casp3 Cancer Research Results

H2S, hydrogen sulfide: Click to Expand ⟱
Features:
Hydrogen sulfide (H₂S), a gaseous signaling molecule, has been implicated in Alzheimer’s disease (AD) pathology with both neuroprotective and neurotoxic roles, depending on concentration, source, and context.
- It was found that the endogenous H2S level in the brain of AD patients was significantly lower than that of normal people.
-A cysteine-rich diet or supplementation with an appropriate amount of N-acetylcysteine is beneficial to the synthesis of H2S in the brain
-Activates Nrf2, upregulates antioxidant genes Reduces oxidative stress, neuroprotective.
-Inhibits NF-κB activation Suppresses inflammatory cytokines like TNF-α, IL-1β
-Reduces Aβ aggregation and toxicity
-Enhances cerebral blood flow

**Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation.**

Hydrogen sulfide (H₂S) — a small, membrane-permeable gaseous signaling molecule and endogenous gasotransmitter produced principally through cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE/CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST/MPST). It functions as a redox and metabolic signaling mediator, notably through protein persulfidation, modulation of mitochondrial electron transport, vascular signaling, and stress-response pathways. H₂S has a strongly biphasic biological profile: low physiologic concentrations can promote mitochondrial bioenergetics, cytoprotection, proliferation, and angiogenesis, whereas sufficiently high concentrations inhibit mitochondrial Complex IV and can cause energetic collapse and cell death. In cancer this creates an important therapeutic paradox because many tumors exploit increased endogenous H₂S production, while high-output or tumor-targeted H₂S donors are being investigated experimentally as anticancer agents.

Primary mechanisms (ranked):

  1. Protein persulfidation of cysteine residues, altering enzyme activity, signaling, stress responses, DNA repair, and metabolism.
  2. Biphasic mitochondrial regulation: low H₂S can support electron transport and ATP production, whereas high H₂S inhibits cytochrome-c oxidase / mitochondrial Complex IV.
  3. CBS/CSE/3-MST-derived endogenous H₂S can support tumor-cell bioenergetics, proliferation, survival, and angiogenesis.
  4. Redox regulation through glutathione, reactive oxygen species buffering, and Keap1 persulfidation with NRF2 activation.
  5. Modulation of mitochondrial and nuclear DNA repair, including persulfidation-dependent mitochondrial DNA repair mechanisms.
  6. Vascular signaling and vasodilation, including interactions with nitric oxide signaling that can promote tumor perfusion and angiogenesis.
  7. At sufficiently high or rapidly delivered concentrations, mitochondrial respiratory inhibition, ATP depletion, oxidative/metabolic stress, and apoptosis or other forms of cancer-cell death.
  8. Modulation of inflammatory signaling including NF-κB and NLRP3, generally anti-inflammatory under physiologic/cytoprotective conditions but strongly context-dependent in tumors.

Bioavailability / PK relevance: Free H₂S is highly diffusible but extremely short-lived in biological systems because it is rapidly oxidized, scavenged, bound, or incorporated into reactive sulfur species. Experimental studies therefore commonly use NaHS, Na₂S, GYY4137, AP39, SG1002, or other H₂S-releasing compounds rather than administering gaseous H₂S systemically. Release rate, intracellular localization, oxygen tension, sulfide oxidation capacity, and tissue targeting can substantially change biological effects.

In-vitro vs systemic exposure relevance: Concentration is critical. Bolus sulfide salts can transiently produce H₂S concentrations considerably higher than sustained physiologic exposure and therefore may cause mitochondrial inhibition that does not represent endogenous H₂S signaling. Results obtained with high-concentration NaHS or Na₂S should not be interpreted as equivalent to physiologic endogenous H₂S or slow-release donors. Tumor-targeted and mitochondria-targeted donors are intended to overcome this exposure problem.

Clinical evidence status: Preclinical for cancer therapy. Tumor H₂S metabolism is well supported mechanistically in experimental cancer models, but H₂S administration is not an established cancer treatment. H₂S donors and H₂S-generating systems remain investigational. SG1002 has undergone small Phase I human studies primarily in cardiovascular disease, not cancer. No H₂S donor has established clinical efficacy for cancer, and inhaled/free H₂S is a toxic respiratory and mitochondrial poison at sufficiently high exposure.

Hydrogen Sulfide Cancer-Relevant Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 CBS CSE 3-MST H₂S signaling ↑ frequently in selected tumors ↔ physiologic homeostasis G ↑ proliferation and survival Many cancers increase one or more H₂S-generating enzymes. The dominant enzyme is tumor-type dependent; CBS is particularly established in colorectal and ovarian models, while 3-MST and CSE contribute in other cancers.
2 Mitochondrial electron transport and Complex IV ↑ at low H₂S; ↓ at high H₂S ↑ at low H₂S; ↓ at high H₂S P Biphasic bioenergetic regulation Low endogenous H₂S can act as a mitochondrial electron source and support ATP production. High sulfide concentrations inhibit cytochrome-c oxidase and suppress oxidative phosphorylation (dose-dependent).
3 Protein persulfidation ↑ ↑ P–R Post-translational signaling regulation A major signaling mechanism of H₂S and reactive sulfur species. Effects depend on the protein modified and cellular redox environment.
4 Mitochondrial DNA repair ↑ ↔ or ↑ R–G ↑ stress resistance and survival In lung adenocarcinoma, endogenous H₂S supports mitochondrial DNA repair including persulfidation of EXOG and stabilization of mitochondrial DNA-repair complexes.
5 Angiogenesis and tumor perfusion ↑ ↑ vascular relaxation R–G ↑ blood flow and angiogenic signaling Endogenous tumor-derived H₂S can stimulate vascular responses and tumor angiogenesis; interactions with NO signaling are important.
6 ROS and redox buffering ↓ at physiologic levels; ↑ possible at cytotoxic exposure ↓ P–R Redox homeostasis H₂S can increase antioxidant capacity and limit oxidative damage, but high concentrations that disrupt mitochondria can instead promote metabolic and oxidative stress (dose-dependent).
7 Keap1 NRF2 antioxidant signaling ↑ (context-dependent) ↑ R ↑ cytoprotection and antioxidant transcription Persulfidation of Keap1 can release NRF2 and increase antioxidant defenses. This is generally cytoprotective and therefore can potentially protect tumor cells as well as normal tissue.
8 Apoptosis ↓ at low H₂S; ↑ at high H₂S ↓ at physiologic cytoprotective levels R–G Biphasic cell-survival control Endogenous or low donor exposure often suppresses apoptosis. High-output or targeted H₂S delivery may induce mitochondrial dysfunction and cancer-cell death (dose-dependent).
9 NF-κB inflammatory signaling ↓ or mixed ↓ R Anti-inflammatory signaling H₂S can suppress NF-κB-dependent inflammatory signaling, but effects are cell-, dose-, and disease-context dependent.
10 NLRP3 inflammasome ↓ or mixed ↓ R–G ↓ inflammatory activation Generally reported as inhibitory in inflammatory models; its net contribution to tumor immunity is context-dependent.
11 Chemosensitivity ↓ with endogenous H₂S; ↑ when H₂S synthesis is inhibited ↔ G Modulation of treatment resistance Endogenous H₂S can support DNA repair and bioenergetics in some tumors. CBS/CSE/3-MST inhibition can therefore increase chemotherapy sensitivity in experimental models; this does not imply that supplemental H₂S is a chemosensitizer.
12 High-output H₂S cytotoxicity ↑ cell death ↑ toxicity at sufficient exposure P–R Complex IV inhibition and energetic collapse The anticancer concept requires controlled or tumor-selective delivery because the same mechanism can injure normal cells and becomes systemically toxic.
13 Clinical Translation Constraint Context-dependent Dose-limited P–G Delivery and therapeutic-window limitation Rapid sulfide metabolism, narrow concentration-dependent transition between signaling and toxicity, donor-specific PK, tissue oxygenation, tumor heterogeneity, and lack of cancer efficacy trials currently limit translation.

TSF: P: 0–30 min     R: 30 min–3 hr     G: >3 hr



Hydrogen sulfide and Alzheimer’s disease: H₂S is an endogenous neuromodulatory gasotransmitter with substantial preclinical evidence for neuroprotective effects relevant to Alzheimer’s disease. Experimental H₂S replacement or donor treatment can suppress tau hyperphosphorylation, reduce amyloidogenic processing, decrease oxidative and inflammatory injury, and improve cognition in animal models. A particularly well-supported mechanism is persulfidation of GSK3β, which decreases its kinase activity and reduces pathological tau phosphorylation. H₂S biology is nevertheless concentration-dependent, and excessive H₂S can inhibit mitochondrial Complex IV and become neurotoxic.

Clinical evidence status: Preclinical. Cell and transgenic-animal studies support disease-modifying mechanisms, but there is no established H₂S donor therapy for Alzheimer’s disease and no evidence from therapeutic RCTs demonstrating clinical efficacy. Human studies have primarily examined H₂S as a biomarker rather than treatment.

Hydrogen Sulfide Alzheimer-Relevant Mechanisms

Rank Pathway / Axis Modulation TSF Primary Effect Notes / Interpretation
1 GSK3β persulfidation and Tau phosphorylation GSK3β ↓; Tau phosphorylation ↓ R–G ↓ pathological Tau signaling H₂S-dependent persulfidation of GSK3β suppresses kinase activity; loss of this modification has been demonstrated in AD-related experimental systems.
2 Amyloid beta production and accumulation ↓ G ↓ amyloid burden H₂S donors reduced Aβ generation and accumulation in APP/PS1 and related experimental models.
3 BACE1 and amyloidogenic APP processing ↓ G ↓ Aβ production Experimental evidence indicates suppression of BACE1 and PS1-associated amyloidogenic processing.
4 Oxidative stress and ROS ↓ P–R Neuroprotection Physiologic H₂S signaling supports glutathione/redox defense and limits oxidative injury.
5 Keap1 NRF2 antioxidant signaling ↑ R ↑ antioxidant response Keap1 persulfidation can promote NRF2 activation and downstream antioxidant gene expression.
6 Neuroinflammation and NF-κB ↓ R–G ↓ inflammatory injury H₂S suppresses inflammatory cytokine signaling in multiple neural and non-neural experimental systems.
7 NLRP3 inflammasome ↓ R–G ↓ neuroinflammatory activation Consistent with the broader anti-inflammatory actions of physiologic H₂S, although the effect varies with model and dose.
8 Mitochondrial function ↑ at low H₂S; ↓ at high H₂S P Biphasic mitochondrial regulation Physiologic concentrations support mitochondrial function; excessive sulfide inhibits Complex IV and becomes neurotoxic (dose-dependent).
9 Cerebral blood flow and vascular signaling ↑ P–R ↑ neurovascular support Vasodilatory H₂S signaling may improve cerebral perfusion in experimental models.
10 Neuronal apoptosis ↓ at protective concentrations R–G ↑ neuronal survival H₂S donors reduce Aβ-associated and oxidative-stress-associated neuronal apoptosis in preclinical models.
11 Clinical Translation Constraint Context-dependent P–G Unproven human therapeutic efficacy Optimal brain H₂S exposure is unknown; free H₂S has rapid PK and substantial toxicity at high concentrations. No therapeutic AD RCT establishes efficacy or an appropriate clinical dose.

TSF: P: 0–30 min     R: 30 min–3 hr     G: >3 hr
Casp3, CPP32, Cysteinyl aspartate specific proteinase-3: Click to Expand ⟱
Source:
Type:
Also known as CP32.
Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death.
As a key protein of apoptosis, caspase-3 can also cleave GSDME and induce pyroptosis. Loss of caspase activity is an important cause of tumor progression.
Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been puzzling. Recent studies suggest subapoptotic caspase-3 activity may promote oncogenic transformation, a possible explanation for the enigmatic overexpression of PC-3. Herein, the overexpression of PC-3 in cancer and its mechanistic basis is reviewed; collectively, the data suggest the potential for exploitation of PC-3 overexpression with PC-3 activators as a targeted anticancer strategy.
Caspase 3 is the main effector caspase and has a key role in apoptosis. In many types of cancer, including breast, lung, and colon cancer, caspase-3 expression is reduced or absent.
On the other hand, some studies have shown that high levels of caspase-3 expression can be associated with a better prognosis in certain types of cancer, such as breast cancer. This suggests that caspase-3 may play a role in the elimination of cancer cells, and that therapies aimed at activating caspase-3 may be effective in treating certain types of cancer.
Procaspase-3 is a apoptotic marker protein.
Prognostic significance:
• High Cas3 expression: Associated with good prognosis and increased sensitivity to chemotherapy in breast, gastric, lung, and pancreatic cancers.
• Low Cas3 expression: Linked to poor prognosis and increased risk of recurrence in colorectal, hepatocellular carcinoma, ovarian, and prostate cancers.
Scientific Papers found: Click to Expand⟱
7499- H2S,    Hydrogen sulfide slows down progression of experimental Alzheimer's disease by targeting multiple pathophysiological mechanisms
*TNF-α↓, *Bcl-2↑, *BAX↓, *Casp3↓, *Inflam↓, *Apoptosis↓, *memory↑,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Total Targets: 0

Pathway results for Effect on Normal Cells:


Cell Death(tgid=5) ⓘ

Apoptosis↓, 1,   BAX↓, 1,   Bcl-2↑, 1,   Casp3↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

Inflam↓, 1,   TNF-α↓, 1,  

Functional Outcomes(tgid=23) ⓘ

memory↑, 1,  
Total Targets: 7

Scientific Paper Hit Count for: Casp3, CPP32, Cysteinyl aspartate specific proteinase-3
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:346  Target#:42  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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